Pathological cell death occurs in the course of Huntington'sdisease (HD), Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS) and also after acute brain trauma and cerebral ischemia. Drugs that inhibit caspases (enzymes that drive programmed cell death) slow down chronic degenerations and decrease damage following acute insult. Because the release of cytochrome c from mitochondria triggers caspase activation, blocking that critical step should derail the cell death program. Our proposed scheme for drug discovery has five portions which constitute the following five Specific Aims: 1) Testing compounds that inhibit the release cytochrome c for their ability to protect cultured neurons from pro-apoptotic stimuli in four cellular models of neurological disease. 2) Assaying molecular changes (i.e., caspase activation, post-translational changes to Bcl-2 proteins, release from mitochondria of apoptogenic factors, loss of mitochondrial membrane potentials) in these cultured cells. Each compound found to be protective in (1) will be tested for its effects on these biochemical and physiological processes. 3) Testing in an animal model of HD (the R6/2 mouse) those experimental drugs that rescue cultured neurons from cell death. 4) Determining the molecular and physiological changes in the brains of R6/2 mice that result from administration of these drugs. 5) Testing in R6/2 mice whether the beneficial effects of novel drugs add to those of known therapies for HD. The Preliminary Results section shows that minocycline has parallel effects upon isolated mitochondria, cultured neurons, and tissues of the mouse CNS. Such observations motivated a screen of 1040 compounds in an NINDS library for their ability to block cytochrome c release from purified mitochondria. The underlyingassumption is that should other drugs have action similar to minocycline in the cell-free system, they are apt to have comparable neuroprotective effects in vivo. The results of this screen are presented. Additional data on minocycline follows, i.e., that the drug rescues neurons in cellular models of cell death and slows neurological degeneration in R6/2 mice. Using the program outlined above, we hope to identify and characterize other compounds that slow the progress of HD.